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RAS mutations and cetuximab in locally advanced rectal cancer: results of the EXPERT-C trial
F Sclafani1, D Gonzalez1, D Cunningham1
1The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.
Background:
RAS mutations predict resistance to anti-epidermal growthfactor receptor (EGFR) monoclonal antibodies in metastatic colorectal cancer. We analysed RAS mutations in 30 non-metastatic rectal cancer patients treated with or without cetuximab within the 31 EXPERT-C trial.
Methods:
Ninety of 149 patients with tumours available for analysis were KRAS/BRAF wild-type, and randomly assigned to capecitabine plus oxaliplatin (CAPOX) followed by chemoradiotherapy, surgery and adjuvant CAPOX or the same regimen plus cetuximab (CAPOX-C). Of these, four had a mutation of NRAS exon 3, and 84 were retrospectively analysed for additional KRAS (exon 4) and NRAS (exons 2/4) mutations by using bi-directional Sanger sequencing. The effect of cetuximab on study end-points in the RAS wild-type population was analysed.
Results:
Eleven (13%) of 84 patients initially classified as KRAS/BRAF wild-type were found to have a mutation in KRAS exon 4 (11%) or NRAS exons 2/4 (2%). Overall, 78/149 (52%) assessable patients were RAS wild-type (CAPOX, n=40; CAPOX-C, n=38). In this population, after a median follow-up of 63.8months, in line with the initial analysis, the addition of cetuximab was associated with numerically higher, but not statistically significant, rates of complete response (15.8% versus 7.5%, p=0.31), 5-year progression-free survival (75.5% versus 67.5%, hazard ratio (HR) 0.61, p=0.25) and 5-year overall survival (83.8% versus 70%, HR 0.54, p=0.20).
Conclusions:
RAS mutations beyond KRAS exon 2 and 3 were identified in 17% of locally advanced rectal cancer patients. Given the small sample size, no definitive conclusions on the effect of additional RAS mutations on cetuximab treatment in this setting can be drawn and further investigation of RAS in larger studies is warranted.
Insights
RAS mutations in rectal cancer patients can affect treatment outcomes. Further research is needed to confirm the impact of these mutations on cetuximab efficacy in larger studies.
Area of Science:
- Oncology
- Molecular Biology
- Clinical Trials
Background:
- RAS mutations are known predictors of resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies in metastatic colorectal cancer.
- This study investigated RAS mutations in patients with non-metastatic rectal cancer treated with or without cetuximab as part of the EXPERT-C trial.
Purpose of the Study:
- To analyze RAS mutations in locally advanced rectal cancer patients.
- To evaluate the effect of cetuximab on treatment endpoints in the RAS wild-type population.
Main Methods:
- Retrospective analysis of RAS mutations (KRAS exon 4, NRAS exons 2/4) using bi-directional Sanger sequencing in 84 patients initially classified as KRAS/BRAF wild-type.
- Patients were randomly assigned to capecitabine plus oxaliplatin (CAPOX) with or without cetuximab (CAPOX-C).
Main Results:
- Eleven (13%) of 84 patients had mutations in KRAS exon 4 or NRAS exons 2/4.
- Overall, 52% of assessable patients were RAS wild-type.
- In the RAS wild-type population, cetuximab showed numerically higher but not statistically significant rates of complete response, 5-year progression-free survival, and 5-year overall survival.
Conclusions:
- RAS mutations beyond KRAS exon 2 and 3 were identified in 17% of locally advanced rectal cancer patients.
- Due to the small sample size, definitive conclusions on the effect of additional RAS mutations on cetuximab treatment cannot be drawn.
- Further investigation of RAS mutations in larger studies is warranted to clarify their role in this setting.
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